Most drugs which humans abuse serve as positive reinforcers to maintain and strengthen behavior leading to their administration in animals. Experiments are being conducted to assess neuropharmacological and behavioral mechanisms underlying drug-seeking and drug-taking behavior in rats and monkeys and the ability of pharmacological or behavioral manipulations to modify such behavior. Currently, studies are focusing on methamphetamine, cocaine, methohexital and selegiline (l-deprenyl). In one study the role of different neurotransmitter systems in the reinforcing effects of methamphetamine was evaluated in rats trained to i.v. self-administer methamphetamine. We found that pretreatment with methamphetamine dose dependently decreased subsequent methamphetamine self-administration. Similar effects were observed when the dopamine releaser phentermine was used. This corresponds with biochemical findings in a parallel study showing that methamphetamine self- administration produces changes in dopamine receptor levels in different brain regions and is in line with the generally accepted hypothesis that dopaminergic neurotransmission plays a crucial role in rewarding effects of drugs. However, in other studies establishing effects of different serotonergic and histaminergic agents on methamphetamine self-administration, even more robust effects were observed when rats were pretreated with either serotonin or histamine releasers or with the serotonin-uptake inhibitor fluoxetine. This suggests that dopamine does not play an exclusive role in mediating methamphetamines reinforcing effects and that drugs modulating other neurotransmitter systems, or histaminergic systems, might be effective in the treatment of methamphetamine abuse. In another study, squirrel monkeys were trained to i.v. self-administer d-amphetamine under a second-order schedule in which drug-seeking behavior was reinforced by a single i.v. injection of drug at the end of the daily session. Moderate rates of self-administration behavior were maintained by selegilline and high rates of behavior by its enatiomer d-deprenyl. In other studies monkeys were trained to self-administer either cocaine or methohexital, and the abuse liability of the benzodiazepine midazolam was evaluated. Midazolam maintained much higher levels of self- administration in methohexital-trained subjects than in cocaine-trained subjects, suggesting that the pharmacological history of individuals plays an important role in the development of benzodiazepine dependence. Finally, we are continuing our studies on combining stimuli associated with drug administration. Previous studies have shown that combining stimuli associated with cocaine self-administration leads to an increase in both drug-seeking and drug-taking and that similar effects are observed for the classically conditioned effects of cocaine. In addition to cocaine, similar enhancements in drug-seeking and drug-taking are observed for heroin self-administration. Thus, these effects can probably be generalized to many classes of abused drugs and appear to be related to the incentive-motivational properties" of the drugs tested. These studies show that combining stimuli associated with drug-taking can be expected to potentiate any conditioned effects and thus may accelerate drug-taking or exacerbate the consequences for drug abuse. - methamphetamine, nicotine, cocaine, self-administration, classical conditioning, rats, monkeys